SUMMARY/ABSTRACT Chronic, non-cancer pain is a significant unmet health need worldwide. The prevalence of chronic pain among adults in the United States has been estimated at between 11 and 43%. The personal toll of living with chronic pain is immense, and the economic impact can be devastating. One of the most widely used treatments for chronic pain is opioid analgesics. While the appropriate use of opioids can be an important and effective part of pain management, the United States is currently facing a national crisis resulting from widespread opioid addiction, believed to be the direct product of overprescription. Importantly, there is evidence of a pathological interaction between opioids and the immune system that can contribute to both opioid tolerance and elevated levels of pain. Chronic pain conditions for which opioids are most often prescribed have been shown to involve dysregulation of the immune system, which may contribute to pathological effects of opioid use in these patients. To ensure proper treatment and restrict opioids to those conditions for which they will be most effective without further exacerbation of pain, it will be essential to identify the underlying pathophysiology driving pain in a given patient. Importantly, there are currently no unbiased, mechanism-based methods for pain diagnosis. Given the variability in self-reported pain measurements and unclear etiology of a majority of chronic pain conditions, an objective tool that could identify the nature of pain and stratify patients into treatment groups would be an important advancement in medicine. In particular, identifying patients who would be ill-suited for opioid treatment would have a major impact on public health. To address this unmet need, we propose to develop a reliable, cost effective and non-invasive in vitro diagnostic assay for chronic pain with an underlying inflammatory pathology. This blood test will be available to primary care physicians and results will be clear and actionable. In this Phase I application, we will use phage display biopanning and next generation sequencing to identify peptides that bind autoantibodies uniquely associated with patients who have widespread chronic pain. We will identify a unique peptide signature that can be used to objectively identify patients with these biomarkers and develop a prototype peptide array that is capable of reproducibly detecting a specific set of antibodies from serum. In Phase 2, we plan to use the chronic pain peptide signature to further develop a clinically useful array specific for determining the presence of a pain-related autoantibody signature. Affinergy?s device for objectively identifying an inflammation-induced chronic pain signature will play an important role in assessing pain and distinguishing those patients who should not receive opioids as a first line treatment.